Fan Jianping, Zhao Jian, Shao Jie, Wei Xianzhao, Zhu Xiaodong, Li Ming
Department of Orthopedics, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China.
Department of Orthopedics, Handan 285 Hospital, Handan, Hebei 056000, P.R. China.
Exp Ther Med. 2017 Nov;14(5):4602-4606. doi: 10.3892/etm.2017.5032. Epub 2017 Aug 25.
Ankylosing spondylitis (AS) is characterized by osteoclastogenesis and inflammatory bone resorption. The present study aimed to investigate the effect of bromodomain and extra-terminal domain (BET) protein inhibitor I-BET151 on AS process. A total of 38 AS Chinese patients were recruited and a further 38 sex- and age-matched healthy participants were selected as control. The Bath AS Function Index and Bath AS Disease Activity Index were assessed in AS patients and levels of erythrocyte sedimentation rate and C-reactive protein were measured in AS and healthy groups. Serum from AS patients was used to induce MG63 osteoblasts and BET inhibitor I-BET151 at concentrations of 50, 100 and 200 ng/ml used for treatment of the cells. A HLA-B27/β2m transgenic AS Lewis rat model was established and treated with 30 mg/kg I-BET151 for 5 weeks. Levels of receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), matrix metalloproteinase (MMP)3, and MMP9 were measured using ELISA and additionally detected with western blotting and polymerase chain reaction . The levels of RANKL, OPG, MMP3 and MMP9 were upregulated in AS serum, AS serum treated MG63 cells and HLA-B27/β2m transgenic AS rats. Conversely, levels of RANKL, OPG, MMP3 and MMP9 were significantly inhibited in cells or animals treated with I-BET151. Overall, the results of the present study demonstrated that BET inhibitor I-BET151 suppresses levels of RANKL, OPG, MMP3 and MMP9 in AS and . I-BET151 may exhibit the potential to be used as a therapeutic in the treatment of AS patients.
强直性脊柱炎（AS）的特征是破骨细胞生成和炎性骨吸收。本研究旨在探讨溴结构域和额外末端结构域（BET）蛋白抑制剂I-BET151对AS进程的影响。共招募了38例中国AS患者，并选取另外38例年龄和性别匹配的健康参与者作为对照。对AS患者评估巴斯强直性脊柱炎功能指数和巴斯强直性脊柱炎疾病活动指数，并测定AS组和健康组的红细胞沉降率及C反应蛋白水平。用AS患者的血清诱导MG63成骨细胞，并使用浓度为50、100和200 ng/ml的BET抑制剂I-BET151处理细胞。建立HLA-B27/β2m转基因AS刘易斯大鼠模型，并用30 mg/kg I-BET151治疗5周。使用酶联免疫吸附测定法（ELISA）测量核因子κB受体活化因子配体（RANKL）、骨保护素（OPG）、基质金属蛋白酶（MMP）3和MMP9的水平，并另外通过蛋白质印迹法和聚合酶链反应进行检测。RANKL、OPG、MMP3和MMP9水平在AS血清、经AS血清处理的MG63细胞以及HLA-B27/β2m转基因AS大鼠中上调。相反，在经I-BET151处理的细胞或动物中，RANKL、OPG、MMP3和MMP9水平受到显著抑制。总体而言，本研究结果表明，BET抑制剂I-BET151可抑制AS中RANKL、OPG、MMP3和MMP9的水平。I-BET151可能具有用作治疗AS患者的治疗药物的潜力。
